In the United States alone, approximately 500,000 deaths will result from rupture of plaques considered "insignificant" on an angiographic evaluation. Available screening and diagnostic methods are insufficient to identify possible victims before the event occurs. Therefore, there is a definite and urgent clinical need for an imaging technique that can identify and characterize the vulnerability of atherosclerotic plaques during coronary artery interventions. The overall goal of our research program is to develop an in-vivo imaging technology - combined intravascular ultrasound and photoacoustic imaging - capable of visualizing both structural and functional properties of atherosclerotic plaques. The underlying hypothesis of this project is that intravascular photoacoustic (IVPA) imaging combined with intravascular ultrasound (IVUS) imaging is possible and can be used to distinguish vulnerable plaques, thus assisting pre-intervention planning, the intervention itself, and improving the post-intervention outcome. Most importantly, the proposed photoacoustic imaging will not significantly change the current protocol of coronary artery intervention. A wide range of scientific and engineering, biomedical and clinical problems must be addressed to fully explore the capabilities of intravascular photoacoustic imaging in interventional cardiology. The central theme of the current project is to develop and test the prototype of the combined IVUS/IVPA in- vivo imaging system prior to extensive clinical studies. Therefore, the main objective of our multi- disciplinary application is to develop an in-vivo, minimally invasive, functional and even molecular specific imaging technology - combined IVUS/IVPA imaging - capable of immediate and accurate assessment of the presence and vulnerability of atherosclerotic plaques at critical stages. To achieve our objective, first we will design and build a prototype of the IVUS/IVPA imaging system based on an available IVUS imaging systems and catheters interfaced with a tunable laser source. Furthermore, we will develop the signal/image processing algorithms and optimize the performance of the system. Second, we will develop a novel molecularly sensitive contrast agent appropriate for the IVUS/IVPA imaging system. Third, we will test the developed IVPA/IVUS imaging technology in tissue-mimicking phantoms, 3-D cell tissue constructs, small animal model of atherosclerosis, and, lastly, excised human tissue. Finally, based on the insights gathered during the project, we will design the intensive animal and clinical studies to demonstrate that the IVUS/IVPA imaging system may become a superior clinical imaging tool needed in interventional cardiology. PUBLIC HEALTH RELEVANCE: Atherosclerotic cardiovascular disease results in more than 19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify possible victims before the event occurs - in the United States alone, approximately 500,000 deaths per year will result from rupture of plaques considered "insignificant" on an angiographic evaluation. There is a definite and urgent clinical need for a technique that can a) identify the presence and location of atherosclerotic plaques, b) characterize pathologic features that predict plaque rupture including large lipid collection within the plaque, thinning of the fibrous cap, and infiltration of macrophages at the shoulders of the fibrous cap, and c) guide coronary artery interventions including percutaneous balloon angioplasty, endovascular stenting, ablation/vaporization and brachytherapy. To address this clinical need, we propose to develop an advanced, catheter-based combined ultrasound and photoacoustic imaging technique capable of visualizing functional properties of atherosclerotic plaques. Therefore, the overall goal of our research program is to develop an in-vivo, minimally invasive, functional and even molecular specific imaging technology - combined IVUS/IVPA imaging - capable of immediate and accurate assessment of presence and vulnerability of atherosclerotic plaques at critical stages. A wide range of scientific and engineering, biomedical and clinical problems must be addressed to fully test IVUS/IVPA imaging. The central theme of the current application is threefold: to design and build a prototype of the IVUS/IVPA imaging system, to develop novel molecularly sensitive contrast agent appropriate for IVUS/IVPA imaging system, and to initially test the developed IVPA/IVUS imaging technology in tissue-mimicking phantoms, 3-D cell tissue constructs, small animal model of atherosclerosis, and, finally, excised human tissue. The current study is designed to demonstrate that in-vivo IVUS/IVPA imaging is practical and feasible. At the conclusion of this study and in cooperation with industrial partners, we will be ready to build the clinical IVUS/IVPA imaging system demonstrating the application of developed technology in interventional cardiology.